Hereditary Angioedema
Conditions
Keywords
HAE
Brief summary
The purpose of this study was to evaluate the safety and efficacy of donidalorsen in participants with HAE and effect of donidalorsen on the quality and pattern of HAE attacks and their impact on quality of life (QoL).
Detailed description
This was a Phase 3, multi-center, double-blind, randomized, placebo-controlled study of donidalorsen in 91 participants. Participants were randomly assigned in a 2:1 ratio to Cohort A (donidalorsen or placebo every 4 weeks) or Cohort B (donidalorsen or placebo every 8 weeks), respectively. Within each Cohort, participants were randomized in a 3:1 ratio to receive donidalorsen or matching-placebo. The study included an up to 8-week Screening Period, a 24-week Treatment Period, and an up to 13-week Post-treatment Period.
Interventions
DRUGDonidalorsen
Donidalorsen was administered by SC injection.
DRUGPlacebo
Donidalorsen-matching placebo was administered by SC injection.
Sponsors
Ionis Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria 1. Participants, or their legally appointed and authorized representatives, must provide written and signed informed consent form (ICF)/assent 2. Participants must be aged ≥ 12 years at the time of informed consent and, as applicable, assent 3. Participants must have a documented diagnosis of hereditary angioedema type 1 (HAE-1)/hereditary angioedema type 2 (HAE-2) 4. Participants must: 1. Experience a minimum of 2 HAE attacks (confirmed by the Investigator) during the Screening Period 2. Be willing to complete the participant reported outcomes (PRO) assessments throughout the study 5. Participants must have access to, and the ability to use acute medication(s) to treat angioedema attacks Key
Exclusion criteria
1. Concurrent diagnosis of any other type of recurrent angioedema, including acquired, idiopathic angioedema or HAE with normal C1-INH (also known as HAE Type III) 2. Any clinically-significant abnormalities in screening laboratory values that would render a participant unsuitable for inclusion in the study 3. Treatment with another investigational drug or biological agent within 1 month or 5 half-lives, whichever is longer, of Screening 4. Participated in a prior ISIS 721744 study 5. Exposure to any of the following medications: 1. Angiotensin-converting enzyme (ACE) inhibitors or any estrogen containing medications with systemic absorption within 4 weeks prior to Screening 2. Chronic prophylaxis with Takhzyro, Haegarda, Cinryze and Ruconest or Orladeyo within 5 half-lives prior to Screening 3. Oligonucleotides (including small interfering ribonucleic acid \[siRNA\]) within 4 months of Screening if single dose received, or within 12 months of Screening if multiple doses received. This exclusion does not apply to vaccines 6. Recent history (3 years) of, or current drug or alcohol abuse
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time-Normalized Investigator-Confirmed (IC) HAE Attack Rate (Per Month) From Week 1 to Week 25 | Week 1 to Week 25 | The time-adjusted HAE attack rate was calculated as number of IC HAE attacks occurring from Week 1 to Week 25, divided by the number of days the participant contributed to the period multiplied by 28 days. An HAE attack was defined as an event with signs or symptoms consistent with an attack in at least 1 of the locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of IC HAE Attack-Free Participants From Week 5 to Week 25 | Week 5 to Week 25 | An HAE attack was defined as an event with signs or symptoms consistent with an attack in at least 1 of the locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx). Percentages are rounded off to the nearest decimal. |
| Time-Normalized Moderate or Severe IC HAE Attack Rate (Per Month) From Week 5 to Week 25 | Week 5 to Week 25 | The time-adjusted HAE attack rate was calculated as number of investigator-confirmed moderate or severe HAE attacks occurring from Week 5 to Week 25, divided by the number of days the participant contributed to the period multiplied by 28 days. An HAE attack was defined as an event with signs or symptoms consistent with an attack in at least 1 of the locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx). |
| Number of Participants With a Clinical Response From Week 5 to Week 25 | Week 5 to Week 25 | Clinical response was defined as a ≥ 50%, ≥ 70%, or ≥ 90% reduction from Baseline in HAE attack rate from Week 5 to Week 25. The HAE attack rate between Week 5 and Week 25 for each participant is calculated as number of HAE attacks occurring from Week 5 to week 25 divided by the number of days the participant contributed to the period multiplied by 28 days. An HAE attack was defined as an event with signs or symptoms consistent with an attack in at least 1 of the locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx). Baseline= Run-in period which is the period from screening to the last day prior to Study Day 1. |
| Time-Normalized IC HAE Attack Rate (Per Month) From Week 5 to Week 25 | Week 5 to Week 25 | The time-adjusted HAE attack rate was calculated as number of IC HAE attacks occurring from Week 5 to Week 25, divided by the number of days the participant contributed to the period multiplied by 28 days. An HAE attack was defined as an event with signs or symptoms consistent with an attack in at least 1 of the locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx). |
| Percentage of Participants Who Are Well Controlled on the Angioedema Control Test (AECT) at Week 25 | Week 25 | The AECT is a validated participant-reported outcome instrument to assess disease activity in participants with recurrent angioedema. The questionnaire consists of 4 questions asking about the frequency and severity of angioedema experienced in last 4 weeks. Each question has 5 response choices with total score ranging from 0 to 16. The AECT can be used to identify participants with poorly controlled disease by working with a cutoff value of greater than or equal to 10 points. Participants who score less than 10 points (0-9) in the AECT have poorly controlled disease whereas participants with well-controlled disease score 10-16 points. Percentages are rounded off to the nearest decimal. |
| Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at Week 25 | Week 25 | The AE-QoL questionnaire is a validated tool to assess symptom-specific health-related QOL impairment in participants suffering from recurrent angioedema. It is a self-administered questionnaire comprising 17 questions across 4 domains: functioning, fatigue/mood, fears/shame, and food. The responses are scored from 0 to 4 where, 0 = never, 1 = rarely, 2 = occasionally, 3 = often, 4 = very often. The AE-QoL domain scores and total score were calculated by using the following formula: (Sum score of all completed items) / (maximum sum score of all possible items) × 100. Total scores ranges from 0 to 100, with higher scores indicating greater impairment. Negative change from baseline indicates improvement. The calculated domain and total scores were not raw scores but linear transformations to a 0 to 100 scale. Baseline is defined as the score on Study Day 1. |
| IC HAE Attack Rate Requiring Acute HAE Therapy From Week 5 to Week 25 | Week 5 to Week 25 | Time-adjusted HAE attack rate is calculated as number of IC HAE attacks requiring acute therapy occurring from Week 5 to Week 25, divided by number of days the participant contributed to period multiplied by 28 days. An HAE attack was defined as an event with signs or symptoms consistent with an attack in at least 1 of the locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx). HAE attacks requiring acute therapy included those attacks with following concomitant medications c1 esterase inhibitors (human and recombinant), plasma kallikrein inhibitor (human), and bradykinin antagonist. |
Countries
Belgium, Bulgaria, Canada, Denmark, France, Germany, Israel, Italy, Netherlands, Poland, Spain, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 39 investigative sites from 3 December 2021 to 09 November 2023.
Pre-assignment details
A total of 91 participants were enrolled and randomized in the study. Out of 91, 1 participant withdrew consent prior to receiving the study drug. As pre-specified in the protocol and statistical analysis plan, for purposes of analysis, data for placebo participants from Cohort A and Cohort B was pooled for comparison to donidalorsen treated participants.
Participants by arm
| Arm | Count |
|---|---|
| Pooled Placebo Participants with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) either every 4 weeks (Week 1, 5, 9, 13,17, and 21) or 8 weeks (Week 1, 9, and 17). | 22 |
| Cohort A: Donidalorsen 80 mg Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21. | 45 |
| Cohort B: Donidalorsen 80 mg Participants with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17. | 23 |
| Total | 90 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Pregnancy | 1 | 0 | 0 |
| Overall Study | Roll Over to CS7 | 19 | 44 | 20 |
| Overall Study | Voluntary Withdrawal | 2 | 1 | 0 |
Baseline characteristics
| Characteristic | Pooled Placebo | Cohort A: Donidalorsen 80 mg | Cohort B: Donidalorsen 80 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 35.4 years STANDARD_DEVIATION 11.03 | 39.6 years STANDARD_DEVIATION 15.23 | 34.1 years STANDARD_DEVIATION 13.22 | 37.2 years STANDARD_DEVIATION 13.88 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 3 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 43 Participants | 20 Participants | 84 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaskan Native | 2 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Race Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Black or African American | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Multiple | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Other | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White | 18 Participants | 42 Participants | 22 Participants | 82 Participants |
| Sex: Female, Male Female | 8 Participants | 28 Participants | 12 Participants | 48 Participants |
| Sex: Female, Male Male | 14 Participants | 17 Participants | 11 Participants | 42 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 45 | 0 / 23 |
| other Total, other adverse events | 15 / 22 | 22 / 45 | 13 / 23 |
| serious Total, serious adverse events | 1 / 22 | 0 / 45 | 0 / 23 |
Outcome results
Primary
Time-Normalized Investigator-Confirmed (IC) HAE Attack Rate (Per Month) From Week 1 to Week 25
The time-adjusted HAE attack rate was calculated as number of IC HAE attacks occurring from Week 1 to Week 25, divided by the number of days the participant contributed to the period multiplied by 28 days. An HAE attack was defined as an event with signs or symptoms consistent with an attack in at least 1 of the locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx).
Time frame: Week 1 to Week 25
Population: The FAS included all randomized participants who received at least 1 dose of the study drug (donidalorsen or placebo). As pre-specified in the protocol and statistical analysis plan, for purposes of analysis, data for placebo participants from Cohort A and Cohort B was pooled for comparison to donidalorsen treated participants.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pooled Placebo | Time-Normalized Investigator-Confirmed (IC) HAE Attack Rate (Per Month) From Week 1 to Week 25 | 2.26 HAE attacks per month |
| Cohort A: Donidalorsen 80 mg | Time-Normalized Investigator-Confirmed (IC) HAE Attack Rate (Per Month) From Week 1 to Week 25 | 0.44 HAE attacks per month |
| Cohort B: Donidalorsen 80 mg | Time-Normalized Investigator-Confirmed (IC) HAE Attack Rate (Per Month) From Week 1 to Week 25 | 1.02 HAE attacks per month |
Comparison: The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each participant was observed from Week 1 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used to account for potential over dispersion.p-value: <0.00195% CI: [0.107, 0.351]Poisson regression model
Comparison: The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each participant was observed from Week 1 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used in the Poisson regression model to account for potential overdispersion.p-value: =0.00495% CI: [0.261, 0.777]Poisson regression model
Secondary
Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at Week 25
The AE-QoL questionnaire is a validated tool to assess symptom-specific health-related QOL impairment in participants suffering from recurrent angioedema. It is a self-administered questionnaire comprising 17 questions across 4 domains: functioning, fatigue/mood, fears/shame, and food. The responses are scored from 0 to 4 where, 0 = never, 1 = rarely, 2 = occasionally, 3 = often, 4 = very often. The AE-QoL domain scores and total score were calculated by using the following formula: (Sum score of all completed items) / (maximum sum score of all possible items) × 100. Total scores ranges from 0 to 100, with higher scores indicating greater impairment. Negative change from baseline indicates improvement. The calculated domain and total scores were not raw scores but linear transformations to a 0 to 100 scale. Baseline is defined as the score on Study Day 1.
Time frame: Week 25
Population: The FAS included all randomized participants who received at least 1 dose of the study drug (donidalorsen or placebo). Overall number of participants analyzed is the number of participants with data available for analysis at the specified time point. As pre-specified in the protocol and statistical analysis plan, for purposes of analysis, data for placebo participants from Cohort A and Cohort B was pooled for comparison to donidalorsen treated participants.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pooled Placebo | Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at Week 25 | -6.19 Score on a scale |
| Cohort A: Donidalorsen 80 mg | Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at Week 25 | -24.76 Score on a scale |
| Cohort B: Donidalorsen 80 mg | Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at Week 25 | -19.85 Score on a scale |
p-value: <0.00195% CI: [-27.673, -9.454]Mixed model with repeated measures(MMRM)
p-value: =0.0195% CI: [-24.024, -3.286]MMRM
Secondary
IC HAE Attack Rate Requiring Acute HAE Therapy From Week 5 to Week 25
Time-adjusted HAE attack rate is calculated as number of IC HAE attacks requiring acute therapy occurring from Week 5 to Week 25, divided by number of days the participant contributed to period multiplied by 28 days. An HAE attack was defined as an event with signs or symptoms consistent with an attack in at least 1 of the locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx). HAE attacks requiring acute therapy included those attacks with following concomitant medications c1 esterase inhibitors (human and recombinant), plasma kallikrein inhibitor (human), and bradykinin antagonist.
Time frame: Week 5 to Week 25
Population: The FAS included all randomized participants who received at least 1 dose of the study drug (donidalorsen or placebo). As pre-specified in the protocol and statistical analysis plan, for purposes of analysis, data for placebo participants from Cohort A and Cohort B was pooled for comparison to donidalorsen treated participants.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pooled Placebo | IC HAE Attack Rate Requiring Acute HAE Therapy From Week 5 to Week 25 | 1.80 HAE attacks per month |
| Cohort A: Donidalorsen 80 mg | IC HAE Attack Rate Requiring Acute HAE Therapy From Week 5 to Week 25 | 0.15 HAE attacks per month |
| Cohort B: Donidalorsen 80 mg | IC HAE Attack Rate Requiring Acute HAE Therapy From Week 5 to Week 25 | 0.59 HAE attacks per month |
Comparison: The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each participant was observed from Week 5 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used in the Poisson regression model to account for potential over dispersion.p-value: <0.00195% CI: [0.03, 0.234]Poisson regression model
Comparison: The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each participant was observed from Week 5 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used in the Poisson regression model to account for potential over dispersion.p-value: =0.00495% CI: [0.155, 0.706]Poisson regression model
Secondary
Number of Participants With a Clinical Response From Week 5 to Week 25
Clinical response was defined as a ≥ 50%, ≥ 70%, or ≥ 90% reduction from Baseline in HAE attack rate from Week 5 to Week 25. The HAE attack rate between Week 5 and Week 25 for each participant is calculated as number of HAE attacks occurring from Week 5 to week 25 divided by the number of days the participant contributed to the period multiplied by 28 days. An HAE attack was defined as an event with signs or symptoms consistent with an attack in at least 1 of the locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx). Baseline= Run-in period which is the period from screening to the last day prior to Study Day 1.
Time frame: Week 5 to Week 25
Population: The FAS included all randomized participants who received at least 1 dose of the study drug (donidalorsen or placebo). As pre-specified in the protocol and statistical analysis plan, for purposes of analysis, data for placebo participants from Cohort A and Cohort B was pooled for comparison to donidalorsen treated participants.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pooled Placebo | Number of Participants With a Clinical Response From Week 5 to Week 25 | ≥ 90% Reduction | 2 Participants |
| Pooled Placebo | Number of Participants With a Clinical Response From Week 5 to Week 25 | ≥ 50% Reduction | 6 Participants |
| Pooled Placebo | Number of Participants With a Clinical Response From Week 5 to Week 25 | ≥ 70% Reduction | 4 Participants |
| Cohort A: Donidalorsen 80 mg | Number of Participants With a Clinical Response From Week 5 to Week 25 | ≥ 50% Reduction | 42 Participants |
| Cohort A: Donidalorsen 80 mg | Number of Participants With a Clinical Response From Week 5 to Week 25 | ≥ 70% Reduction | 37 Participants |
| Cohort A: Donidalorsen 80 mg | Number of Participants With a Clinical Response From Week 5 to Week 25 | ≥ 90% Reduction | 28 Participants |
| Cohort B: Donidalorsen 80 mg | Number of Participants With a Clinical Response From Week 5 to Week 25 | ≥ 90% Reduction | 11 Participants |
| Cohort B: Donidalorsen 80 mg | Number of Participants With a Clinical Response From Week 5 to Week 25 | ≥ 70% Reduction | 15 Participants |
| Cohort B: Donidalorsen 80 mg | Number of Participants With a Clinical Response From Week 5 to Week 25 | ≥ 50% Reduction | 19 Participants |
Comparison: ≥ 50% Reductionp-value: <0.00195% CI: [11.63, 8279.94]Regression, Logistic
Comparison: ≥ 50% Reductionp-value: <0.00195% CI: [3.15, 69.41]Regression, Logistic
Comparison: ≥ 70% Reductionp-value: <0.00195% CI: [7.32, 164.87]Regression, Logistic
Comparison: ≥ 70% Reductionp-value: =0.00495% CI: [2.05, 41.09]Regression, Logistic
Comparison: ≥ 90% Reductionp-value: <0.00195% CI: [3.36, 86.42]Regression, Logistic
Comparison: ≥ 90% Reductionp-value: =0.01495% CI: [1.56, 48.52]Regression, Logistic
Secondary
Percentage of IC HAE Attack-Free Participants From Week 5 to Week 25
An HAE attack was defined as an event with signs or symptoms consistent with an attack in at least 1 of the locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx). Percentages are rounded off to the nearest decimal.
Time frame: Week 5 to Week 25
Population: The FAS included all randomized participants who received at least 1 dose of the study drug (donidalorsen or placebo). As pre-specified in the protocol and statistical analysis plan, for purposes of analysis, data for placebo participants from Cohort A and Cohort B was pooled for comparison to donidalorsen treated participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pooled Placebo | Percentage of IC HAE Attack-Free Participants From Week 5 to Week 25 | 9.1 Percentage of participants |
| Cohort A: Donidalorsen 80 mg | Percentage of IC HAE Attack-Free Participants From Week 5 to Week 25 | 53.3 Percentage of participants |
| Cohort B: Donidalorsen 80 mg | Percentage of IC HAE Attack-Free Participants From Week 5 to Week 25 | 34.8 Percentage of participants |
p-value: =0.00395% CI: [2.34, 59.36]Regression, Logistic
p-value: =0.2495% CI: [0.46, 22.85]Regression, Logistic
Secondary
Percentage of Participants Who Are Well Controlled on the Angioedema Control Test (AECT) at Week 25
The AECT is a validated participant-reported outcome instrument to assess disease activity in participants with recurrent angioedema. The questionnaire consists of 4 questions asking about the frequency and severity of angioedema experienced in last 4 weeks. Each question has 5 response choices with total score ranging from 0 to 16. The AECT can be used to identify participants with poorly controlled disease by working with a cutoff value of greater than or equal to 10 points. Participants who score less than 10 points (0-9) in the AECT have poorly controlled disease whereas participants with well-controlled disease score 10-16 points. Percentages are rounded off to the nearest decimal.
Time frame: Week 25
Population: The FAS included all randomized participants who received at least 1 dose of the study drug (donidalorsen or placebo). Overall number analyzed is the number of participants with data available for analysis at the specified timepoint. As pre-specified in the protocol and statistical analysis plan, for purposes of analysis, data for placebo participants from Cohort A and Cohort B was pooled for comparison to donidalorsen treated participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pooled Placebo | Percentage of Participants Who Are Well Controlled on the Angioedema Control Test (AECT) at Week 25 | 47.1 Percentage of participants |
| Cohort A: Donidalorsen 80 mg | Percentage of Participants Who Are Well Controlled on the Angioedema Control Test (AECT) at Week 25 | 92.9 Percentage of participants |
| Cohort B: Donidalorsen 80 mg | Percentage of Participants Who Are Well Controlled on the Angioedema Control Test (AECT) at Week 25 | 77.3 Percentage of participants |
Secondary
Time-Normalized IC HAE Attack Rate (Per Month) From Week 5 to Week 25
The time-adjusted HAE attack rate was calculated as number of IC HAE attacks occurring from Week 5 to Week 25, divided by the number of days the participant contributed to the period multiplied by 28 days. An HAE attack was defined as an event with signs or symptoms consistent with an attack in at least 1 of the locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx).
Time frame: Week 5 to Week 25
Population: The FAS included all randomized participants who received at least 1 dose of the study drug (donidalorsen or placebo). As pre-specified in the protocol and statistical analysis plan, for purposes of analysis, data for placebo participants from Cohort A and Cohort B was pooled for comparison to donidalorsen treated participants.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pooled Placebo | Time-Normalized IC HAE Attack Rate (Per Month) From Week 5 to Week 25 | 2.25 HAE attacks per month |
| Cohort A: Donidalorsen 80 mg | Time-Normalized IC HAE Attack Rate (Per Month) From Week 5 to Week 25 | 0.30 HAE attacks per month |
| Cohort B: Donidalorsen 80 mg | Time-Normalized IC HAE Attack Rate (Per Month) From Week 5 to Week 25 | 0.90 HAE attacks per month |
Comparison: The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each participant was observed from Week 5 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used in the Poisson regression model to account for potential over dispersion.p-value: <0.00195% CI: [0.062, 0.281]Poisson regression model
Comparison: The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each participant was observed from Week 5 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used in the Poisson regression model to account for potential over dispersion.p-value: =0.00495% CI: [0.212, 0.748]Poisson regression model
Secondary
Time-Normalized Moderate or Severe IC HAE Attack Rate (Per Month) From Week 5 to Week 25
The time-adjusted HAE attack rate was calculated as number of investigator-confirmed moderate or severe HAE attacks occurring from Week 5 to Week 25, divided by the number of days the participant contributed to the period multiplied by 28 days. An HAE attack was defined as an event with signs or symptoms consistent with an attack in at least 1 of the locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx).
Time frame: Week 5 to Week 25
Population: The FAS included all randomized participants who received at least 1 dose of the study drug (donidalorsen or placebo). As pre-specified in the protocol and statistical analysis plan, for purposes of analysis, data for placebo participants from Cohort A and Cohort B was pooled for comparison to donidalorsen treated participants.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pooled Placebo | Time-Normalized Moderate or Severe IC HAE Attack Rate (Per Month) From Week 5 to Week 25 | 1.15 HAE attacks per month |
| Cohort A: Donidalorsen 80 mg | Time-Normalized Moderate or Severe IC HAE Attack Rate (Per Month) From Week 5 to Week 25 | 0.12 HAE attacks per month |
| Cohort B: Donidalorsen 80 mg | Time-Normalized Moderate or Severe IC HAE Attack Rate (Per Month) From Week 5 to Week 25 | 0.68 HAE attacks per month |
Comparison: The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each participant was observed from Week 5 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used in the Poisson regression model to account for potential over dispersion.p-value: <0.00195% CI: [0.035, 0.339]Poisson regression model
Comparison: The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each participant was observed from Week 5 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used in the Poisson regression model to account for potential over dispersion.p-value: =0.17395% CI: [0.276, 1.26]Poisson regression model